Ewing sarcoma

Ewing sarcoma is a rare cancer that can form in bone in 85% of cases and soft tissue. It belongs to a group of tumours known as the Ewing sarcoma family of tumours.

The Ewing family of tumours includes:

Ewing sarcoma - a form of primary bone cancer
Extraosseous Ewing sarcoma - a tumour that starts in soft-tissue rather than the bone
Askin tumour - Ewing sarcoma that starts in the chest wall
Primitive Neuroectodermal Tumour - Ewing sarcoma where the cells look like nerve cells when studied under the microscope

Ewing sarcomas is the second most commonly diagnosed primary bone cancer in children and young people, after osteosarcoma.

Ewing sarcoma can start anywhere in body, but more often it is found in the pelvis, the chest or in the bones of the legs.

Figure 1. Where does Ewing Sarcoma occur most often?

Diagram of skeleton showing where Ewing's sarcoma most often occurs

Image: Hannah Thompson

Ewing sarcoma arises from any part of the bone with almost equal frequency. Ewing sarcoma is more commonly found in flat bones e.g. the ribs or the pelvis.

Figure 2. What are the different parts of a long bone?

Diagram showing structure inside a long bone relating to Ewing's sarcoma

Image: Hannah Thompson

Ewing sarcoma can spread to other parts of the body

Ewing sarcoma can quickly spread to other parts of the body and can sometimes come back after treatment (recur).

Tumour cells can break away from the primary tumour and enter the blood supply or lymphatic system. These tumour cells can travel to other parts of the body where they can settle and form new tumours called secondary tumours or metastases. The tumour cells can also spread through the bone as the tumour grows.

The most common sites for secondary tumours are:

the lungs
other bones
the bone marrow

Very rarely the cancer can spread to the lymph nodes, liver or brain.

Treatment is usually a combination of chemotherapy, surgery and radiotherapy. Wherever the Ewing sarcoma develops in the body, the treatment is the same.

There are fewer than 100 cases of Ewing sarcoma diagnosed in the UK and Ireland each year.
In the general population in Europe each year, there are slightly less than two cases of Ewing sarcoma diagnosed per million people (1.90 / 1,000,000). This is known as the incidence rate.
In the USA, the incidence rate is higher than the European rate at 2.9 cases per million people.
Ewing sarcoma can occur at any age but it is very rare in people over the age of 30.
The peak of incidence (between 10 and 20 years of age) of Ewing sarcoma patients corresponds with times at which a person's bones are growing fastest. The average age of patients with Ewing sarcoma is 15-years old.
Ewing sarcoma occurs more often in males compared to females. However, in the 0-14 age group, males and females appear to be equally affected.
Ewing sarcoma accounts for around 1.5% of all childhood cancers.
Survival rates for Ewing sarcoma have not significantly improved over the past 30 years.

There has been a lot of research into possible causes of Ewing sarcoma but the exact cause remains unknown.

The development of Ewing sarcoma may be related in some way to periods of rapid bone growth. This may explain why most cases of Ewing sarcoma are seen in adolescents.

Risk factors for Ewing sarcoma

There are no known inherited risk factors (hereditary factors) that cause Ewing sarcoma.

There is no confirmed link between any environmental factors and Ewing sarcoma.

More information

Age: Most cases of Ewing sarcoma are diagnosed between the ages of 10 and 24-years old.
Race: Ewing sarcoma seems to be less common in people of African-Caribbean or Chinese origin, compared with Caucasian people.

Can Ewing sarcoma be prevented?

As the causes of Ewing sarcoma are not fully understood, we don't know how to prevent it from happening.

There has been a lot of research into the biology of Ewing sarcoma in recent years, in order to help us to understand what causes cells to become cancerous; however there are still many un-answered questions. Recent research has been moving our knowledge forward but only very slowly.

We do know that cells contain important information in their chromosomes called genes, which instruct cells on how to divide and grow normally. Damage to certain genes can cause a cell to behave differently and grow abnormally, which can then lead to development of cancer.

We know that almost all Ewing sarcoma patients share the same kind of gene damage, although we don't know what causes this damage to happen.

Genes are made of a molecule called DNA. In cells, DNA is found in long strings called chromosomes. Each chromosome is made up of thousands of genes, one after another. We know that in Ewing sarcoma there is a chromosomal translocation - this means that a part of a chromosome has broken off and stuck to the wrong chromosome, or sometimes there is a swap of sections of DNA between one chromosome and another.

Translocations put the genes in the wrong order along a chromosome and this can mean that genes are switched on and off wrongly, in a way that can cause cancer or other illnesses.

Chromosomes

In figure 1, you can see the chromosomes in a human cell. Humans have 23 pairs of chromosomes. Each pair contains 1 copy from the mother and one copy from the father (this is how we can inherit traits from both parents). One pair of chromosomes forms the 'sex chromosomes', and if a person has XY they are male or if they have XX they are female.

The chromosomes have are been given a number from 1 to 22 (the sex chromosomes are number 23). Chromosome 1 is the longest, 2 is slightly shorter, and so on to number 22, which is the shortest.

Figure 1. The full set of human chromosomes, which are long strings of DNA.

Diagram showing a full set of human chromosomes

Figure 2 shows a microscope picture that shows the chromosomes as strings in the centre of a cell.
The study of chromosomes is carried out by scientists known as cytogeneticists (SY-tow-geh-NET-eh-sist).

Figure 2. Microscope image of cells showing visible chromosomes inside the cells.

microscope image showing chromosomes inside human cells

Chromosome translocations

In around 95% of Ewing sarcoma cases, there is a translocation between chromosomes, and we know that this translocation causes the cancer to start.

The particular translocation in Ewing sarcoma, PNET and Askin tumour is usually where a part of chromosome 11 has moved to chromosome 22 and a piece of chromosome 22 has moved to chromosome 11.

You may see this written as t(11;22)(q24;q11) when you are reading about Ewing sarcoma. The 't' stands for translocation and the numbers in the first brackets tell us which chromosomes are involved. The second bit in brackets tells us what part of the chromosome is involved. Some Ewing sarcoma patients have slightly different genetic changes. These are the translocations described as t(21;22)(q22;q12), t(7;22), t(17;22) or t(2;22) or a slightly different genetic change called inv(22).

How do chromosome translocations cause problems in cells?

When a translocation occurs, it interferes with the genes. Genes can be broken when the chromosomes break, so the genes can't do their usual job in the cell. Alternatively, two genes can be stuck together where the chromosomes join together. This fuses two genes together, making a so called 'fusion gene', which has some properties of each gene. Either of these situations can cause cancer.

In the case of Ewing sarcoma the translocation between chromosomes 11 and 22 joins two genes together, one called EWS and the other called FLI1, to form a 'fusion gene' called EWS-FLI1. Fusion genes are found in different cancers but EWS-FLI1 is specific to the Ewing sarcoma Family of Tumours and can therefore help to confirm the diagnosis of Ewing sarcoma.

The formation of the EWS-FLI1 fusion gene instructs the cell to make EWS-FLI1 fusion protein, which is a 'transcription factor'. Transcription factors are powerful switches in the cell, able to switch many other genes on or off. EWS-FLI1 causes cancer by switching the wrong genes on and off at the wrong times, causing the cell to divide uncontrollably.

The EWS-FLI1 translocation happens only in the cells of the tumour. The translocation does not occur in sperm or egg cells and therefore people with Ewing sarcoma can't pass the translocation on to their children. This means that there is no increased risk of Ewing sarcoma for the children of surviving patients. There is also no increased risk for brothers and sisters of Ewing patients.

Why is research into the biology of Ewing sarcoma important?

Research to identify the exact cell type in which the EWS-FLI1 translocation happens and Ewing sarcoma starts is a big area of research. Knowing this could allow scientists and doctors to work out what causes the chromosome translocations to happen.

Understanding the biology of cancer cells helps doctors and scientists to find new targets for treatment and markers (clues) that can help a patient to be diagnosed quicker. For example, some researchers are trying to make new drugs that target EWS-FLI1 fusion protein, to allow all Ewing sarcoma cells to be killed without harming healthy cells.

When doctors talk about 'presentation', they mean 'symptoms' and 'clinical signs'.

Symptoms and clinical signs

The most reported symptoms of Ewing sarcoma are:

A mass that can be felt (palpable) when undergoing physical examination
Broken bone (fracture) resulting from weakening of bone due to a tumour - a pathological fracture
Bone pain which is worse at night, constant or intermittent, resistant to analgesia and may increase in intensity
Easy bruising
Mobility issues - an unexplained limb, joint stiffness, reduced range of movement
Inflammation and tenderness over the bone or joint can be seen/felt if a tumour is near the skin. Swelling is not always visible because if a tumour is deep inside the body, such as in the pelvis

Less common symptoms include:

fever (known as pyrexia)
tiredness or feeling weary (referred to as lethargy or fatigue)
pain accompanied by tingling and numbness (pins and needles)
weight loss and loss of appetite
breathlessness

Symptoms vary from patient to patient, can range in their severity and there is no definitive list. Symptoms may be mild at first, presenting over a period of a couple of weeks, but they may appear suddenly. Some patients report their symptoms disappearing for relatively long periods before suddenly returning.

Symptoms may be present for weeks or months, sometimes even longer before patients are diagnosed. This can be because the symptoms of Ewing sarcoma are quite general and could indicate a number of conditions. Some examples of these in older children, adolescents and young adults include:

Tendonitis - an inflammation of the tendons.
Osgood-Schlatter disease - inflammation of the growth plate where the kneecap tendon inserts.
Trauma - injury caused by something external e.g. a sports injury.
Slipped epiphysis - where the growing section of a bone at the end of a long bone slips and moves on the bone, which can cause a lot of pain.

In younger children the same symptoms could indicate, amongst other conditions:

Osteomyelitis - an infection of the bone.

As the symptoms are general and could be caused by other conditions, many patients struggle to get a correct diagnosis when they first see a doctor. Many patients experience pain that is intermittent, and this can mislead doctors into thinking that the cause of the pain is temporary. Most patients do not actually feel ill until the cancer is fairly well advanced.

In addition, because most Ewing sarcoma patients are in their teens, the pain is sometimes mistaken for bone growth or 'growing pains'. Patients in this age group are also usually very physically active and the pain may be suspected to be from a sports injury or everyday activities.

Going to the doctor

The symptoms of Ewing sarcoma are general. There is no one clear sign that doctors can easily look for to make a diagnosis of Ewing sarcoma.

People report a variety of experiences when they seek medical advice about their symptoms. Most people with worrying symptoms go to their GP.

Some patients go to their local hospital emergency department (A&E) or other health care centres.

Some people are referred quickly for further tests or a second opinion, but often patients have to return to their GP three or four times before they are referred for more tests. Primary bone cancers are very rare and many GPs will never come across a case.

If a GP or hospital doctor is concerned about the patient's symptoms, there are national guidelines they should follow. According to the National Institute for Clinical excellence (NICE) guidelines for suspected bone cancer and sarcoma:

Children, teenagers and young adults with unexplained bone swelling or bone should have an urgent X-ray within 48 hours. If the X-ray suggests a possible bone cancer, your GP should refer you to a specialist within 48 hours.
Adults should be seen by a specialist within 2 weeks if the results of an X-ray suggest a bone cancer.

If the X-ray is normal but symptoms persist, the patient should be followed up and/or a repeat X-ray or MRI scan should be carried out within 2 weeks (adult) or within 48 hours (child) or a referral requested to a specialist.

Bone Cancer Awareness Initiative

The Bone Cancer Research Trust is trying to find ways to make the time between the start of symptoms and getting the diagnosis much shorter. Our 2020 Patient Survey report is the most comprehensive analysis of presenting symptoms and routes to diagnosis for primary bone cancers & tumours in the UK to date. This is our evidence base on which we will focus our awareness objectives moving forward.

The report focuses on two main areas - the time and routes to diagnosis and the range of presenting symptoms across all anatomical locations and forms of primary bone cancer & bone tumours.

Our analysis found that patients wait, on average, more than 7 months and make 8 visits to the multiple healthcare professionals before receiving an accurate diagnosis.

Going to a Bone Cancer Centre for more tests

Once an abnormality is found in a bone that suggests the possibility of cancer, the patient will be referred to a bone cancer surgical centre.

Bone cancer surgical centres are specialist hospitals. They have a group of healthcare specialists who are experts in the diagnosis and management of bone cancer.

In England, there are currently five bone sarcoma centres which specialise in the diagnosis and management of primary bone cancers. These centres are at Birmingham, Newcastle, Oswestry, Oxford, and Stanmore.

In the Republic of Ireland, there are no specific Bone Cancer Centres. Patients are initially seen in their local hospital and subsequently referred to specialist hospitals in Dublin or Cork for further tests and, if necessary, for treatment.

Patients in Wales usually travel to Oswestry or Birmingham for these specialist tests.

In Scotland there are five sarcoma centres and so patients travel to one of these centres for diagnosis if primary bone cancer is suspected. These centres are in Edinburgh, Glasgow, Inverness, Aberdeen and Dundee.

In Northern Ireland, patients are usually seen in Belfast.

For a full list of locations patients may be referred to in order to confirm a primary bone cancer diagnosis please click here

The MDT

Specialists in many different areas of medicine at the bone cancer centres, the Regional Cancer Centres in the UK and hospitals in Ireland work together as a 'Multidisciplinary Team' (MDT). The members of the MDT work together to diagnose the patient's condition.

The MDT includes:

Specialist bone sarcoma surgeons.
Specialist sarcoma oncologists (oncologists are doctors who look after people with cancer).
Specialist sarcoma pathologists (pathologists are doctors who use laboratory techniques to diagnose disease).
Radiologists (doctors who diagnose disease and conditions from looking at x-rays, or scans).
Sarcoma cancer nursing specialists (sometimes called 'CNS') who perform an essential role in treating and caring for primary bone cancer patients.

What tests are done?

When a person is referred to a bone sarcoma surgical centre, further tests will be done to find out more and to confirm whether the patient has bone cancer, and if so what type.

These tests may include:

X-ray

X-rays of the bone may be taken, including the joints above and below, and are studied. These X-rays may show swelling around the bone or areas of abnormal bone growth. A chest x-ray is sometimes taken to show whether the cancer has spread to the lungs.

Cancer Research UK gives more information about X-rays.

Blood tests

These include:

Blood chemistry (Urea and Electrolytes) is checked to examine the levels of normal salts and urea and creatinine, which are waste products. This test can give clues to how well the kidneys are working
Full blood count (FBC) counts the numbers of different types of blood cells in the patient's blood at that time.
Red blood cells - which carry oxygen in the blood.
White blood cells - which are essential to the immune system (and totals of each type).
Platelets - which are essential to the making blood clots and scabs.
Levels of haemoglobin - which is found in red blood cells.
Liver function tests (LFTs) to see how the liver is working.
Erythrocyte Sedimentation Rate (ESR) is a test to look for signs of inflammation.
C-Reactive Protein (CRP) levels are tested as CRP levels increase in inflammation.
Alkaline phosphatase (ALP) levels are measured in patients with suspected osteosarcoma.

Cancer Research UK gives more information about blood tests.

MRI scan

MRI stands for 'magnetic resonance imaging'. This type of scan is similar to a CT scan but magnetism and radio waves are used instead of x-rays to build up a very detailed 3-dimensional image.

An MRI scan of the entire bone is used to gain more information about the tumour in the bone. An injection of a special dye, known as a contrast agent is also used. This makes certain tissues show up more clearly and with greater detail on the scan. The results of the scan will be examined by a radiologist and a report will be produced. For some patients they may also have a total body MRI scan to look for areas of abnormalities in the other bones such as tumour spread (metastases).

Cancer Research UK gives more information about MRI scans.

CT scan

CT stands for 'computerised tomography'. They may also be called CAT scans, which stands for 'computerised axial tomography'.

The scanner takes x-rays from many different angles and a computer builds up a 3-dimensional picture of the body in great detail. The pictures show cross-sections of the inside of the body.

CT scanning of the lungs shows up any secondary tumours where the cancer may have spread (metastases). It is used if the MRI scan results have not been able to confirm the diagnosis of osteosarcoma.

Cancer Research UK gives more information about CT scans.

PET scan

PET stands for 'positron emission tomography.' Not all hospitals have PET scanners but they are used to detect spread or metastases in osteosarcoma.

PET scans can examine the whole body, rather than a specific area. They can also detect how well treatments are working.

Before the scan, a small injection of radioactive glucose (a radiotracer) called fluorine18 will be given.

The tracer will take around an hour to spread around the body. During the scan, which can last about an hour, the patient lies on a bed and the scanner passes over them. The scanner detects where the radiation is concentrated and produces images. Hot spots on the PET scan can detect metastases.

The results of the scan will be examined by a radiologist.

Cancer Research UK gives more information about PET scans.

Biopsy

A bone biopsy is a specialised procedure that can be performed by a specialist in orthopaedic surgery or sarcoma radiology at a bone sarcoma surgical centre. A biopsy involves taking a small sample of a lump or tumour so that a pathologist can examine the cells in the sample and determine whether the lump is cancerous or not.

The biopsy being taken may be one of two types:

Needle biopsy: a needle is inserted into the tumour to draw out a small amount of tumour tissue (this may be done under local anaesthetic). Often, in order to know exactly where to take the sample from, this test is carried out alongside an X-ray or CT scan to guide the doctor.

Open biopsy (or surgical biopsy): is used less frequently than a needle biopsy. This form of biopsy is carried out during a small, minor, operation to remove a small piece of tumour while under general anaesthetic. This test tends to be used if a needle biopsy does not provide a diagnosis and the doctor wish to investigate further.

Cancer Research UK gives more information about bone biopsies.

Where will treatment take place?

Surgery needs to take place at one of the bone sarcoma surgical centres (see map below, blue stars). Chemotherapy and radiotherapy can take place at different hospitals around the UK and Republic of Ireland. The delivery of intensive chemotherapy should be administered at one of the specialised cancer centres. For patients whose nearest specialist hospital is far away, a 'shared care' arrangement for acute issues and unexpected admissions with a closer hospital might be set up. The specialist hospital can be reached for advice on acute presentations and outpatient management.

England and Wales

Diagnosis and surgery should take place in one of the five Bone Cancer Centres (see the map below):

Scotland

Patients are treated at one of the five Sarcoma Centres that are part of the Scottish Sarcoma Network. These hospitals are in Aberdeen, Dundee, Edinburgh, Glasgow, and Inverness. Patients visit one of these five Sarcoma Centres for chemotherapy or radiotherapy treatment. For surgery, primary bone cancer patients are seen in Glasgow, Edinburgh or Aberdeen.

Republic of Ireland

Most patients aged under 16 receiving chemotherapy fare treated at Our Lady's Hospital, Crumlin, Dublin.

Patients aged 15-19 are treated at Mater Misercordiae Hospital, Our Lady's Hospital, Crumlin and Waterford Regional Hospital.

Patients aged over 20 are treated at Mater Misercordiae Hospital, Our Lady's Hospital Crumlin, Sligo General Hospital, Cork University Hospital, Waterford Regional Hospital, St Vincent's Hospital and Mercy Hospital.

For surgery, most patients in the Republic of Ireland (all ages) go to St. Marys Orthopaedic, Cappagh. For radiotherapy most patients attend St Luke's and St Anne's Hospital, Dublin. However, some patients may also attend other hospitals in Dublin and Cork.

Map of UK and Ireland showing location of specialist bone cancer treatment centres

Key

Red stars: Specialist Children's Cancer and Leukaemia Centre
Blue stars: Bone sarcoma surgical centre
Green stars: Children and Young People's Integrated Cancer Service
Purple stars: Teenage Cancer Trust Unit
Yellow stars: Scottish Sarcoma Network Hospital

Please see our full list of centres providing treatment for primary bone cancer here.

What kind of treatment is used for Ewing sarcoma?

Treatment for Ewing sarcoma involves treatment to the whole body with chemotherapy (systemic therapy), and treatment of the tumour site with surgery and radiotherapy (local therapy).

Each Ewing sarcoma patient has a slightly different treatment plan, depending on the stage of their disease and where in their body the cancer started.

Your doctor (oncologist) is the best person to describe to you the treatment choices. Your doctors will also tell you what is to be expected from the treatment.

Treatment of cancer involves patients and the doctors working together to find a care or treatment plan that fits your needs.

Treatment: Overview

In the UK and Ireland, the standard treatment is to give the patient a series of different treatments, usually in this order:

Chemotherapy to shrink the tumour
Surgery to remove the tumour
Radiotherapy to kill any remaining tumour cells (although not every patient being treated for Ewing sarcoma will receive radiotherapy)
Chemotherapy to kill any cancer cells that might have escaped from the tumour
Follow-up monitoring to make sure the cancer has gone.

Phase 1- Neoadjuvant Chemotherapy

Chemotherapy given before surgery is called neoadjuvant chemotherapy.

Following diagnosis and tests, patients are given a combination of chemotherapy drugs before surgery. Following the results of Euro Ewing 2012, an international trial for the treatment of Ewing sarcoma, the standard chemotherapy regime now given to treat Ewing sarcoma is now globally recognised as VDC/IE.

Phase 2 - Surgery

Following a number of cycles of chemotherapy, the main tumour site is treated. Where possible this means that the patients have surgery to remove the primary tumour. This is more likely to be possible if the main (primary) tumour is in a limb (arm or leg) or easily accessible position in the body. For many patients the main tumour may not be easily removable, for example, if the tumour is in the pelvis or spine.

Phase 3 - Pathology

When the tumour is removed, it is examined under a microscope by the pathologist, to make sure that the tumour has been completely removed and to find out how much of the tumour has been killed. The results of this examination may affect treatment after surgery.

Phase 4 - Radiotherapy

After surgery, radiotherapy is given if:

Not all the tumour is completely removed.
More than 10% of the tumour is still alive when examined under a microscope.

The exact dose and length of radiotherapy treatment will also be decided by a special team of doctors, but it is usually given as a single dose each day (a few minutes) for approximately 5 – 6 weeks. In some cases, radiotherapy is given before surgery.

Proton beam therapy

Proton beam therapy is a type of radiotherapy that uses beams of 'protons' (energised particles) instead of beams of X-rays (photons), that are used in conventional radiotherapy. It is more targeted than conventional radiotherapy so does less damage to the healthy tissue surrounding the tumour and other organs.

Phase 5 - Adjuvant Chemotherapy

Chemotherapy will usually continue after surgery and will be given during any radiotherapy treatment that the patient requires. This makes sure that any cancer cells that could have escaped from the primary tumour. are killed before they have a chance to grow into new tumours.

At diagnosis, 25-30% of patients have evidence that their cancer has spread to the lungs, other bones, or to the bone marrow.

If there is evidence that the tumour has spread to other parts of the body then an oncologist and surgeon may consider removing the secondary cancers by surgery.

Treatment: In Detail

Chemotherapy before surgery (Neoadjuvant Chemotherapy)

The standard chemotherapy for Ewing sarcoma is now internationally recognised as the VDC/IE arm from the Euro Ewing 2012 trial (EE2012), both pre and post-operatively. The combination of chemotherapy drugs (sometimes called a 'regime' or 'protocol') given prior to surgery are:

Vincristine, Doxorubicin & Cyclophosphamide
Ifosfamide & Etoposide

Usually chemotherapy lasts for 14 cycles and is given every 2-3 weeks. Most patients have surgery after cycle 9 with a 2 week gap to recover from surgery. Your surgeon and oncologist will inform you when your surgery will be as it can depend on whether patients require radiotherapy. Some patients have surgery after 9 cycles, some after all of their chemotherapy.

Drugs are given in a combination to maximise their effect. If the cancer stops responding to one of the drugs, then the aim is that the other drugs will still be effective in killing the cancer cells.

Current clinical trials for Ewing sarcoma

rEEcur: a trial for the treatment of Ewing sarcoma that has come back after treatment (recurrent) or is not responding to treatment (refractory). The trial is comparing four treatments, also known as regimes or arms. These are:

We also advise you to enquire with an Experimental Cancer Medical Centre. There are different centres across the UK.

We encourage you to discuss any trials with your oncologist, having a printout to refer to at your next clinic/ telephone appointment.

Surgery

The decision about whether surgery is possible is made by the MDT.

The aim of surgery is to remove the primary tumour safely and maintain function as much as possible.

Surgeons have developed different surgical techniques to remove bone tumours whilst preserving the function of the limb. The main technique is replacement of the affected bone with a metal implant and false joint. Another technique is to carry out an autologous (aw-TOH-low-gus) bone graft in which a piece of healthy bone is taken from the patient to replace the bone that has been damaged by a tumour.

Other surgical techniques include resection alone (where just the tumour is removed), allografts (where donated tissue is used to rebuild the limb) and irradiation/ re-implantation, which is where the bone that contains the tumour is removed and treated with radiation. This kills any tumour cells inside the bone, and so the bone can be safely put back into the patient.

Despite these advances in surgical techniques around 10% of patients require an amputation (removal of the limb) to safely remove the tumour. Wherever possible a prosthetic (artificial) limb can be made for the patient. Amputation may also be needed if the cancer has spread to major blood vessels or nerves or if the patient develops a bad infection or other serious complications after limb-sparing surgery

When compared with other bone tumours, Ewing sarcomas respond well to radiotherapy. Sometimes when surgical removal is not possible, radiotherapy can be used alone to kill the cancer cells at the primary tumour site.

Surgery may also be used to remove secondary tumours, such as tumours in the lungs.

Surgery may be needed in future if the reconstruction of the limb wears out or if the tumour comes back.

Radiotherapy

Radiotherapy is a type of 'local therapy', meaning that it is designed to treat the tumour and not the whole body. Radiotherapy involves using a focussed beam of energy to kill the cancer cells that make up the tumour.

The energy used in radiotherapy is a high-energy form of X-rays. The energy beam damages the DNA inside the cancer cells inside the tumour, and this DNA damage prevents the cells from dividing, and causes the cells to die.

Radiotherapy is administered by a radiation oncologist. Radiotherapy is usually given as a single dose each day (a few minutes) for approximately 5 – 6 weeks.

Radiotherapy is sometimes used pre-operatively or instead of surgery, in cases where surgical removal of the primary tumour is not be possible, for example if the tumour is in the pelvis or spine. Radiotherapy may also be used after surgery if not all the tumour is completely removed or more than 10% of the tumour is still alive when examined under a microscope.

Patients who receive radiotherapy may experience unpleasant side-effects from this treatment. These side effects can include:

Proton Beam Therapy

Proton beam therapy is a type of radiotherapy that uses beams of 'protons' (energised particles) instead of beams of X-rays (photons), that are used in conventional radiotherapy. It is more targeted than conventional radiotherapy so does less damage to the healthy tissue surrounding the tumour and other organs. This is advantageous for some primary bone cancers where the cancer is close to a critical part of the body such as the spinal cord or pelvis. Click here for more information on proton beam therapy.

What is the difference between PBT and radiotherapy?

As proton beam therapy is highly targeted towards the tumour, it means it is often possible to treat areas closer to very sensitive structures such as the spinal cord. Overall, this means that fewer healthy cells nearby receive a dose of radiation. This is particularly important in children, whose bodies and structures are still developing.

Who might benefit from it?

The main advantage of PBT is that it can deliver a more targeted use of radiotherapy than x-ray radiotherapy.

This is particularly beneficial to children and young adults with a primary bone cancer, as it avoids damaging healthy, developing tissues and is thought to reduce the risk of secondary malignancies later in life.

For adults, it is considered beneficial for tumours in areas where surrounding tissue is highly sensitive to the effects of radiation. For example, primary bone cancers in a sharply defined areas such as Ewing sarcomas, osteosarcomas of the spine or pelvis as well as chordomas are often suitable for PBT.

Side effects?

One of the key advantages of proton beam therapy over conventional radiotherapy is that it is more targeted. It does less damage to the healthy tissue around the tumour and the rest of the brain. This means it causes fewer side-effects, however, there are a few side-effects which are not uncommon.

The following side-effects are usually temporary and often disappear after treatment has finished:

fatigue
redness that resembles sunburn - this can appear in the area where the proton beam was directed
hair loss.

How can I access PBT?

PBT is now available in UK through NHS. There is an NHS Centre at the Christie Hospital, Manchester as well as a second NHS PBT Centre planned for University College Hospital London (UCLH) due to open soon in 2021.

Costs involved

All PBT is approved by the Proton Clinical Reference Panel. The NHS will cover the cost of PBT treatment at approved treatment centres, whether in the UK or in the USA, Germany and Switzerland. If sent abroad for PBT, it will also fund economy travel and approved accommodation for the patient (children) and one to two carer(s)/parent(s) and one parent/carer for teenage and adult patients, accompanying them.

The NHS will not fund any meals or refreshments, nor any upgrades to travel or accommodation. If you need help to cover travel costs not subsidised by the NHS, contact our Support & Information Service about our Travel Assistance Grant and other financial help that may be available.

Chemotherapy after surgery (Adjuvant Chemotherapy)

Internationally the current standard chemotherapy treatment for Ewing sarcoma after surgery is made up of:

Ifosfamide and Etoposide
Vincristine and Cyclophosphamide

Chemotherapy (or 'chemo' for short) is the name for drugs used for the treatment of cancer. These drugs kill cancer cells or stop their growth by interfering with the way cells divide and grow (also known as the cell cycle), or by damaging the cell's DNA (instructions).

Cancer cells are different to healthy cells because the cancer cells divide very rapidly. This fact is exploited by chemotherapy drugs, which target only rapidly dividing cells. Different chemotherapy drugs achieve this by targeting slightly different parts of the machinery that makes cells divide, and so often these different drugs are used together in combinations, to hit different parts of the cancer cell at the same time. This is called combination chemotherapy.

Most healthy cells do not divide very rapidly. However, some types of healthy cell do divide rapidly, and these include hair follicle cells, skin cells, bone marrow cells, and the cells lining the digestive system. This means chemotherapy drugs can also affect these healthy quick-dividing cells and this is what causes the side effects that are associated with chemotherapy treatment.

Side effects can be unpleasant, such as nausea, diarrhoea, hair loss, mouth sores, an unusual taste in the mouth and tiredness (fatigue). Medications can be given before and after chemotherapy to help with some of these side effects.

There are tips on some good websites about dealing with side effects:

Coping with hair loss: Teenage Info on Cancer (TIC) and Teenage Cancer Trust
Mouth sores and eating problems: Teenage Cancer Trust and Macmillan
Former osteosarcoma patient, Megan Blunt has written a book filled with tips on how to cope with chemotherapy. It's called Chemotherapy, Cakes and Cancer is available to download as a PDF published by CLIC Sargent.

How is chemotherapy given?

There are different ways patients are given chemotherapy; tablets, liquid medicine, injection or directly into the blood. When a patient is given chemotherapy directly into their blood, the drug is given through a cannula (venflon), which is a flexible thin plastic tube that sits in a vein in the arm or hand. Alternatively, patients may have a central line, PICC (peripherally inserted central catheter) or implantable ports (Portacath®).

Portacaths®, PICCs and central lines can be kept in for weeks or even a few months. These lines enable the number of needles required during treatment to be minimised and more than one drug or treatment (such as fluids or nutrition) can be given at the same time because the lines can have multiple openings or 'lumens'.

Because central lines, PICCs and Portacaths® are all slightly different; the decision on which type of line will best suit the patient will be discussed by the nurses and the doctor in the medical team.

Diagram showing location of a chemotherapy central line in the body

Figure 1(a). A central line, also known as a Hickman line.

Image Courtesy of The Christie NHS Foundation Trust.

Diagram showing the location of a peripherally inserted catheter in the body for chemotherapy treatment

Figure 1(b). Peripherally Inserted Central Catheter (PICC).

Image Courtesy of The Christie NHS Foundation Trust.

Diagram showing the location of an implantable port in the body for chemotherapy

Image Courtesy of The Christie NHS Foundation Trust.

The chemotherapy drugs enters the blood through the cannula by an infusion usually called a drip. An infusion or drip is a method of giving a set amount (dose) of I.V. (IntraVenous) medications such as chemotherapy over a set period. This period can be hours or days. The infusion can also be controlled by an infusion pump, which is connected to a central line or a PICC line. Some of the pumps are small enough to fit in a pocket meaning that patients can use them at home.

Chemotherapy is given in 'cycles.' A cycle is the treatment time plus a resting time. For example, a patient may be given a combination of chemotherapy drugs over 3-4 days and then there may be a resting period of 2½ weeks. Therefore, the cycle is 3 weeks long. The resting period helps the healthy cells of the body to recover before the next treatment cycle begins.

High dose chemotherapy with autologous stem cell transplant

Some Ewing sarcoma patients may be offered high dose therapy with an autologous stem-cell transplant. Stem cells are the 'master cells' of the body, they are able to divide many times to make specialised cells that can replace damaged cells in the body. An 'autologous stem cell transplant' is when a patient's own stem cells are collected from their blood, and then stored safely until they are given back to the patient after treatment.

This treatment allows the chemotherapy drugs to be used at a very high dose so that they have the highest possible impact on the cancer. The doses of chemotherapy drugs are so high that they cause serious damage to the cells in the blood, including the red blood cells that carry oxygen and the white blood cells which protect the body from infection. These cells can be replaced by the stem cells that are given back to the patient after treatment.

High dose chemotherapy with autologous stem cell transplant follows this treatment plan:

Stem cell harvest
- Patients are given daily injections (Granulocte-Colony Stimulating Factor) in the run-up to the stem cell harvest. G-CSF is a molecular signal that encourages the production of more stem cells in the blood.
- A blood test is done to test whether the numbers of white blood cells have increased and that the stem cells have moved from their usual home in the bone marrow, into the blood.
- To carry out the harvest an apheresis catheter (a bit like a central line) is inserted into a large vein (either the top of the leg or the neck) in the operating theatre.
- The catheter is linked by two lines to a machine called a cell separator. Blood from the patient passes though one line, into the cell separator. The stem cells are separated out from the blood and the cells are collected in a bag attached to the machine. The patient's blood is then returned to the patient through the second line. The blood in the cell separator is treated with a drug called ACD-A to prevent it from clotting. This drug can have some side effects.
- The number of stem cells collected in the bag will be counted. If there are too few stem cells, the procedure will be repeated the next day.
- The aphresis catheter is removed when the harvest is complete.
- The harvested stem cells are frozen and carefully stored until it is time to give the cells back to the patient.

High dose chemotherapy
- The drugs used for high dose therapy are either Busulphan in combination with melphalan; or treosulphan in combination with melphalan (the second combination has less toxicity and so it is given to patients who have already experienced toxicity from previous treatment such as radiotherapy).
- The high-dose drugs are given over the course of five days. After this there is a day's rest before the stem cells are re-infused.

Autologous stem cell transplant
- One day after the high-dose therapy has finished, the patient's stem cells are infused back into the patient, using a drip.

Patients usually stay in hospital for three to four weeks, as it takes some time for the blood cells to recover. The levels of white blood cells usually get back to normal in around two weeks, but the platelet count can take a bit longer.

Prognosis

The word 'prognosis' refers to what doctors think the chances are of the patient's cancer being cured with treatment or the likelihood of it returning. This depends on many different things, which vary between different patients.

In general, the prognosis for Ewing sarcoma depends on:

The patient's age and general health
The location and size of the Ewing sarcoma
Results of investigations; the stage of the Ewing sarcoma, whether it is localised or metastatic (spread), or recurrent (come back)
How much of the cancer could be removed by surgery
Response to treatment, for example, how effective was chemotherapy prior to surgery
Whether lung (pulmonary) metastases can be removed with surgery (resectable)

Doctors cannot be certain about a patient's prognosis as each patient and each cancer can behave differently.

The overall 5-year survival rate for Ewing sarcoma is around 60%. The term 5-year survival rate can sound quite misleading and worrying to some people. The term does not mean people only lived for 5 years after diagnosis; it refers to the fact that 60 out of every 100 people with Ewing sarcoma are alive 5 years after their diagnosis. These people may not all be cured; some may be still be undergoing treatment.

Follow-up care

After finishing treatment, Ewing sarcoma patients will require follow up care. Outpatient hospital visits will be needed on a regular basis for the first few years after treatment and then probably yearly after that.

These visits will help to keep an eye on a patient's general health as well as an opportunity to carry out some tests. These tests are very important because they can show up any 'late effects' from the cancer treatment. Most centres encourage patients to get in touch if they have problems between appointments.

Follow up care with an orthopaedic surgeon also helps to look out for surgery-related complications and to make sure the limb is working well.

The Children's Cancer and Leukaemia Group (CCLG) provide useful information for children and their parents about what to expect once treatment is finished.

Reaching the end of treatment can bring about mixed emotions. The thought of having no more chemotherapy can be a cause for celebration, but this can be mixed with anxiety about the future. Many emotions can arise surrounding the process of returning to a 'normal' life after cancer.

The CCLG's booklet End of treatment... What happens next? is for 10-16-year olds who have reached the end of their cancer treatment. The booklet deals with many of the emotional issues surrounding the process of returning to a "normal" life after cancer.

A second version of this booklet End of treatment - for parents is available for the parents of a child who has had cancer. This deals with many of the practical issues as well as emotions that might arise when a child reaches the end of their cancer treatment.

For adults who have had treatment for cancer, the issues can be more complex and include workplace and financial issues. Macmillan Cancer Care provides a wealth of useful information on living with and after cancer, which includes information and tips on a broad range of topics.

Relapse and metastases

Relapse means that the cancer has returned. This can be in the same bone as the cancer originally appeared (local relapse) or the cancer can return in a different place, often in the lungs (metastasis).

If the cancer returns it will require more treatment. This will probably involve more chemotherapy and sometimes further surgery. The MDT will be able to advise you on which treatments are necessary.

You may also find Maggie's information on the fear of cancer returning helpful.

Emotional effects

The experience of having cancer can be frightening and stressful, and so the emotional effects of cancer can be as severe as the physical effects.

The Children's Cancer and Leukaemia Group have produced a booklet for teenagers and young adults called After Cure which is full of helpful information for living well after having cancer.

Macmillan Cancer Care has some very useful pages for adults on coping with the emotional aspects of cancer.

Late effects

Most patients experience side effects during their treatments which go away or improve after treatment is ended. However, some side effects become permanent or develop months or years after treatment has ended. These are known as late effects of cancer treatment. More is becoming known about late effects as people are living longer after being treated for cancer.

The late effects of cancer treatment vary depending on the type of cancer, the treatment and surgeries and the age of the patient when undergoing treatment.

However, not everyone who has cancer treatment will necessarily experience late effects. Different chemotherapy drugs cause different late effects and late effects of radiotherapy and surgery will affect only the area of the body exposed to them.

If you were treated for cancer as a child, you may be at risk of the same late effects as people who were adults during their cancer treatments and additional late effects as children's tissues, organs and bones grow rapidly and cancer treatment can interfere with this critical time of growth.

As with late effects in adults, late effects from childhood cancer treatment will vary depending on the type of cancer and type of treatment. Additionally, the age at which you were treated may determine which late effects you might experience.

Signs and Symptoms of Late Effects

You can talk to your doctor or CNS about the late effects of your particular treatment or surgery. They should be able to advise you on which late effects you are at risk from. However, the late effects of many cancer treatments still often go undiagnosed.

At your follow-up appointments you will be screened for late effects of your cancer treatment and surgery. It is also an opportunity to talk to your doctor about any signs or symptoms you may be suffering from and to discuss whether these are late effects.

If you were treated for cancer many years ago or are no longer having follow-up appointments, you should talk to your GP about late effects or contact a Late Effect Clinic.

Late Effects Clinics

If you had your cancer treatment as a child you will be monitored for late effects by your oncology team or a late effects clinic specifically for those patients treated as children.For all other cancer patients, they will be screened by their oncologist whilst under their care but are no longer monitored once they are discharged by their oncology/surgical team.

In September 2014, a late effects clinic was established at Nottingham City Hospital.This Late Effects Clinic is a bespoke service which aims to support people suffering with long-term effects from radiotherapy and chemotherapy and offers practical advice and signposting for a range of physical and psychological effects. It offers a wide range of support and guidance regarding late effects such as bowel and bladder problems, infertility, osteoporosis, sexual dysfunction, pain management and psychological issues to name a few. Patients self-refer and it is open to all patients who are a minimum of 6 months out of treatment. There is no upper limit on time from finishing treatment.

Since this clinic was established, similar clinics have been set up in Derby, Sheffield and Taunton and many more are developing throughout the country.

There is also a Complex Cancer Late Effects Rehabilitation Service based at The Royal National Hospital for Rheumatic Disease in Bath which is a two-week inpatient rehabilitation service for those patients with complex, chronic late effects. Referral to this service is via the late effect clinic or local pain services.

You may find our webinar on the Late Effects Clinic with radiographer, Emma Hallam helpful.

The Bone Cancer Research Trust's information has been compiled using only peer-reviewed clinical and scientific studies, reviews and case studies. Peer-review is a process in which the work of one scientist or doctor is looked at and checked by other experts in the same subject area. The peer-review process helps ensure the science is 'reliable'.

If you are interested in reading deeper into the subject, we have provided a bibliography listing the references and books we used to compile our information about Ewing sarcoma.

Books

Alberts B, Johnson A, Lewis J, Raff M. Molecular Biology of the Cell. Garland Science; 5th edition, 2005. ISBN-10: 0815341059.
Cullinane CJ, Burchill SA, Squire JA, O'Leary JJ, Lewis IJ (eds). Molecular Biology and Pathology of Paediatric Cancer. Oxford University Press. ISBN-10: 0192630792.
Kleihues P, Sobin L, Fletcher C et al, (eds.) WHO Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone, Lyon, France: IARC Press. PDF version download (free)
Mackay J. The chemotherapy and radiotherapy survival guide. New Harbinger Publications, 1998. ISBN 1572240709.
Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available to download here.

Ewing sarcoma: general

Ewing biology

Causes and risk factors

Eyre R, Feltbower RG, Mubwandarikwa E, Eden TO, McNally RJ. Epidemiology of bone tumours in children and young adults. Pediatr Blood Cancer. 2009; 53(6): 941-52.
Jawad MU, Cheung MC, Min ES, Schneiderbauer MM, Koniaris LG, Scully SP. Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005. Cancer. 2009; 115(15): 3526-36.
Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.

Presentation

Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available from here.
Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.
Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000; 82: 667-674.

Diagnosis

Burchill SA. Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003; 56(2): 96-102.
Iwamoto Y. Diagnosis and Treatment of Ewing's sarcoma. Japanese Journal of Clinical Oncology, 2007; 37(2):79-89. Free full text available here.
Kavalar R, Pohar Marinsek Z, Jereb B, Cagran B, Golouh R. Prognostic value of immunohistochemistry in the Ewing's sarcoma family of tumors. Med Sci Monit. 2009; 15(8): CR442-52.
Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
Kleis M, Daldrup-Link H, Matthay K, Goldsby R, Lu Y, Schuster T, Schreck C, Chu PW, Hawkins RA, Franc BL. Diagnostic value of PET/CT for the staging and restaging of pediatric tumors. Eur J Nucl Med Mol Imaging. 2009; 36(1): 23-36.
Lee YY, Kim do H, Lee JH, Choi JS, In KH, Oh YW, Cho KH, Roh YK. Primary pulmonary Ewing's sarcoma/primitive neuroectodermal tumor in a 67-year-old man. J Korean Med Sci. 2007; 22 Suppl:S1, 59-63. Free full text available here.
Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from here.
Machado I, Noguera R, Pellin A, Lopez-Guerrero JA, Piqueras M, Navarro S, Llombart-Bosch A. Molecular diagnosis of Ewing sarcoma family of tumors: a comparative analysis of 560 cases with FISH and RT-PCR. Diagn Mol Pathol. 2009; 18(4): 189-99.
Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available from here.
Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from here.

Treatment

Prognosis

Burchill SA. Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003; 56(2): 96-102.
Cotterill SJ, Ahrens S, Paulussen M, Jürgens HF, Voûte PA, Gadner H, Craft AW.
Prognostic Factors in Ewing's Tumor of Bone: Analysis of 975 Patients From the European Intergroup Cooperative Ewing's sarcoma Study Group. J Clin Oncol. 2000; 3108-3114.
Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12(4): 212-20.
Lahl M, Fisher VL, Laschinger K. Ewing's sarcoma family of tumors: an overview from diagnosis to survivorship. Clin J Oncol Nurs. 2008; 12(1): 89-97.
Lor Randall R. Ewing's sarcoma. An ESUN Article. Liddy Schriver Sarcoma Initiative, 2005. Accessed December, 2009 from: http://sarcomahelp.org/learning_center/ewings_sarcoma.html
Leavey PJ, Collier AB. Ewing sarcoma: prognostic criteria, outcomes and future treatment. Expert Rev Anticancer Ther. 2008; 8(4): 617-24.
Paulussen M, Craft AW. Ewing Tumours: Management and Prognosis in, Education Book, International Society of Paediatric Oncology, 37th Congress of the International Society of Paediatric Oncology Vancouver, British Columbia, Canada - September 20-24, 2005. Available at http://www.cure4kids.org/private/courses_documents/m_148/SIOP-2005-Education-Book.pdf
Rodríguez-Galindo C, Liu T, Krasin MJ, Wu J, Billups CA, Daw NC, Spunt SL, Rao BN, Santana VM, Navid F. Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies. Cancer. 2007; 110(2): 375-84. Free full text available from: http://www3.interscience.wiley.com/cgi-bin/fulltext/114278876/HTMLSTART Strauss LJ. eMedicine article: Ewing's sarcoma. Accessed January 2010 from: http://emedicine.medscape.com/article/389464-overview

This information has been written for patients, their families and friends and the general public to help them understand more about a form of primary bone cancer known as Ewing sarcoma. This section will detail what Ewing sarcoma is and how Ewing sarcoma is diagnosed and treated.

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